Synthesis of steroids



United States Patent 3,294,819 SYNTHESIS OF STEROIDS Gerald W. Krakower, Elizabeth, and Hilda Van Dine, Princeton, N.J., assignors to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Feb. 10, 1966, Ser. No. 526,338 15 Claims. (Cl. 260-3432) This invention is a continuation-in-part of copending application, Serial No. 419,231, filed December 17, 1964, now abandoned.

This invention relates to and has as its object the provision of new physiologically active steroids, novel methods for their production and new intermediates useful in said preparation. More particularly, this invention relates to the preparation of compounds of the formula wherein R is hydrogen; R" is hydroxy or acyloxy; and together R and R' is oxo (0:).

The preferred acyl and acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric and tert-pentanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g., phenacetic and fi-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

[Whenever in this application and the claims appended thereto, a curved line (j is employed in the formulae, it is meant to denote that the connected atom may be either in the alpha or beta position] The final products of this invention are physiologically active steroids which possess uterotrophic activity and may be used in the treatment of such conditions as menstrual disorders, being formulated for such administration in the manner and/or dosage as determined by the respective compound involved and the requirements of the patient.

The final compounds of this invention may be prepared according to the processes of this invention which may be represented by the following equations wherein R and R are as hereinbefore defined and X may be hydrogen,

Y may be hydroxy or acyloxy, and together X and Y is In the first step of the novel process of this invention, the starting materials (Compounds A) are reduced as by treatment with a reducing agent, for example, an alkali metal borohydride, such as sodium borohydride, to yield the 11-hydroxy-16 unsubstituted derivatives thereof. The starting materials (Compounds A) which may be employed in the practice of this invention may be prepared by alkylation of the starting materials corresponding acid to form 21-ester derivatives thereof and treating the ester with ozone to yield the D-ring lactol starting materials of this invention. The disclosure for the preparation of these starting materials is more fully set forth in a prior application, Serial No. 397,015, filed September 16, 1964, in the names of Gerald W. Krakower and Patrick A.

Diassi.

In order to obtain the novel ll-acylated compounds of this invention (Compounds B, VII and VIII), the corresponding ll-hydroxylated compounds may be acylated under acidic conditions, as by treatment with an acid, acid anhydride and toluene sulfonic acid. The 3-hydroxy compounds (Compounds B, III and IV) may be mono-acylated as by treatment with an acylating agent, for example, acid anhydride or acyl halide, in the presence of an organic base, such as collidine or pyridine, to yield the 3-acylated derivatives (Compounds B), which are also new compounds of the instant invention.

The 3,1l-disubstituted compounds may then be oxid ized, as by treatment with an oxidizing agent, for example, chromic acid to yield the 3,11-diketo derivatives (Compounds B), which are new compounds of the instant invention.

In order to obtain the 9a-epimer of the 913,11-keto derivatives (e.g., Compounds B, IX), the 913,1 l-keto compounds are treated with an alcoholic base, for example, ethanolic potassium hydroxide under elevated temperatures to yield the 9fi-epimer (e.g., Compounds B, X), which are also new compounds of this invention.

It has also been found when the starting material (Compounds B, X) is reduced as by treatment with a reducing agent as exemplified hereinabove, the 3 9,171:- dihydroxy and the 3B-hydroxy compounds of this invention are formed. This compound may be acylated in the manner hereinabove set forth.

The invention may be further illustrated by the following examples:

EXAMPLE 1 3oz acetoxy 11cc hydroxy 411,8,14 trimethyl 17- xa-D-hom0-18-nor 5a,8a,95,13a,14fi-androstane-17aone A suspension of 250 mg. of 30:,165 diacetoxy 40:, 8,14 trimethyll7 oxa D homo 18 nor 5og,8ot,9j3, 130:,148 androstane 11,17a dione in 25 ml. of absolute ethanol is treated with 125 mg. of sodium borohydride. and stirred at room temperature. After ten minutes the substrate dissolves and after seventy five minutes the reaction mixture isacidified with glacial acetic acid. The solvent is evaporated and the residue is taken up in ethyl acetate. After washing with saturated salt solution, drying and evaporation of the solvent, 210 mg. of crystalline material is obtained. Two recrystallizations from methanol give 84 mg. of analytically pure 3a-acetoxy-11uhydroxy 4 x,8,14 trimethyl 17 oxa D homo 18- nor- 5u,8oz,9B,13a,l4-fl androstane 17a one, M.P. 209212 C., [11], 55.5.

An'alysis.Calcd for C H O C, 70.37; H, 9.24. Found: C, 70.00; H, 9.66.

EXAMPLE 2 3a acetaxy- 4e',8,14 trimethyl 17 oxa D lwm0 18-n0r-5a,8;8,9u,13a,14fl-androstane-11,17a-di0ne A solution of 48 mg. of 30a acetoxy 11oz hydroxy- 40:,8,14 trimethyl 17 oxa D homo 18 nor- 5a,8or,9,13,13m,14fl'-'androstane 17a one in 2 ml. of acetone is treated with an excess of chromic acid-sulfuric acid reagent. After five minutes at room temperature the excess chromic acid is reduced with methanol and the solution diluted with water. The solvent is evaporated and the aqueous suspension is extracted with methylene chloride. The methylene chloride solution is washed with saturated salt solution, dried and evaporated to give 34 mg. of material. Recrystallization from methanol gives 20 mg. of 30c acetoxy 4a,8,14 trimethyl 17- oxa D homo 18 nor 5a,8a,9,8,13u,14,6 androstanel1,17a-dione, M.P. 214-215 C., 9.4.

Analysis.-C-alcd for C H O C, 70.74; H, 8.78. Found: C, 70.78; H, 8.74.

EXAMPLE 3 3 8 111x dilzydroxy 40:,8,14 trimethyl 17 oxa D- homo 18 nor 5a,8oc,9fi,13ot,14}3 androstane 17aone A suspension of 400 mg. of 166 acetoxy 4a,8,14- trimethyl 17-oxa-D-homo-18-nor 5ot,8a,9B,13uz,14fiandrostane 3,11,17a-trione in 40 ml. of absolute ethanol is treated with 300 mg. of sodium borohydride and stirred at room temperature for three hours. The reaction is then worked up as described in Example 1 to give 373 mg. of crude 318,11a dihydroxy 4rx,8,14 trimethyl- 17 oxa D-homo 18 nor 5ot,8a,9fi,13ot,l4l3 androstane 17a one. Recrystallization from methanol gives 79 mg, M.P. 279-284 C. The analytical sample has M.P. 283-284 C.

Analysis.-Calcd for C H O C, 71.96; H, 9.78. Found: C, 72.00; H, 9.60.

EXAMPLE 4 401,8,14 trimethyl 17 oxa D homo 18 nor 5a, 8u,9,6,13a,14,8-andr0siane-3J1,17a-tri0ne An excess of chromic acid-sulfuric acid reagent is added to a solution of 254 mg. of crude 3fl,11m-dihydroxy 411,8,14 trimethyl l7 oxa D homo 18- nor 5a,8tx,9fl,13a,l4[3 androstane 17a one in 15 ml. of acetone. After fifteen minutes at room temperature, methanol is added to reduce the excess chromic acid and the reaction is worked up as described in Example 2. The 213 mg. of crude 4a,8,14-trimethyl-17- oxa-D-homo18-nor 5a,8a,9i3,13a,14,8-andr0stane-3,1l, 17a-trione obtained is recrystallized from methanol to give a first crop of 94 mg., M.P. 257-260 C. and a second crop of 47 mg, M.P. 246250 C., [111 +103".

Analysis.Calcd for C H O Found: C, 72.94; H, 8.66.

EXAMPLE 5 3a 110a dihydroxy 4a,8,14 trimethyl 17 oxa D- homo 18 nor 5oc,8a,9l3,13oz,14[3 androstane- 17-0ne A solution of 81 mg. of 3c: acetoxy 11cc hydroxy- 4u,8,14 trimethyl 17 oxa D homo 18 nor- 5nt,8a,9/3,l3oz 145 androstane 17a one, in 25 ml. of 5% ethanolic potassium hydroxide is left overnight at room temperature. The solution is then acidified with I 20% sulfuric acid, diluted with water and the solvent evaporated. The aqueous suspension is extracted with ethyl acetate and'washed with saturated salt solution.

dried and evaporated to give 73 mg. of crude 311,111

dihydroxy 4a,8,l4 trimethyl 17 oxa D homo- 18 nor 5oz,8oc,9fl,l3a,14,8 androstane 17a one.

EXAMPLE 6 4a,8,14 trimethyl 17 oxa D homo 18 nor 50c, 8e,9;9,l3a,14fl-andr0slane-3J1,1 7a-trione EXAMPLE 7 4 oc,8,1 4-trimethyl-l 7-0xa-D-h0m0-1 8-710r-50c,8or,] 3a,! 45- androstane-3,11,] 7 a-trione Three hundred forty-two mg. of 4a,8,14-trirnethyl-l7- oxa D homo 18 nor 5a,8oc,9}3,130t, 14p androstane- 3,ll,l7a-trione are added to 35 ml. of a helium blanketed refluxing solution of 5% ethanolic potassium hydroxide. After three hours of reflux under helium, the solution is acidified to pH 3 with 20% sulfuric acid, diluted with Water and the solvent is evaporated. The aqueous residue is extracted with ethyl acetate, washed with water until neutral, dried and evaporated to give 328 mg. of 4a,8,l4- trimethyl 17 oxa-D-homo-l8 -nor-5a,8a,l3a,14,8-androstane-3,11,17a-trione. Recrystallization from methanol gives 210 mg., M.P. 206-210 C., which on further recrystallization gives 138 mg, M.P. 207-211 C., [001, 153 C.

Analysis.-Calcd for C H O C, 72.80; H, 8.73. Found: C, 73.03; H, 8.73.

When 3 a-acetoxy-4a,8,14-trimethyl-17-oxa-D-h0mo-18- nor-5a,8a,9 8,13a,145-androstane-11,17a-dione is treated as described in Example 7, there is obtained 3ot-hydroxy- 4a,8,14 trimethyl-l7-oxa-D-homo-l8-nor-5ot,8u,13a,14,8- androstane-11,17a-dione, which on recrystallization from methanol has M.P. 266-269 C., [M -l79.

'Analysis.Calcd for C H O C, 72.38; H, 9.26. Found: C, 72.33; H, 9.33.

EXAMPLE 9 30c hydroxy 4a,8,14 trimethyl 17 oxa D homo- 18 nor 5et,8a,13ot,14,8 androstane 11,17a dione is acylated with pyridine-acetic anhydride at room temperature to yield 30:. acetoxy 404,8,14 trimethyl 17 oxa- D homo -18 nor 5a,8a,13a,145 androstane 11,17adione, M.P. 200201 C., l80.

Analysis.Calcd for C H O C, 72.74; H, 8.78. Found: D, 72.61; H, 8.81.

EXAMPLE 1O 3 oc,1 1 a-diacetoxy-4vt,8,14-trimethyl-1 7 -xa-D -h0m0-1 8- l10l'-5oc,8a,9[3,1 3 11,1 4,8-andr0stane-1 7 a-one 3a acetoxy 11a hydroxy 4a,8,14 trimethyl 17- oxa D homo 18 nor a,8ot,9[3,13a,14/3 androstane- 17a-one is acylated with a mixture of acetic acid, acetic anhydride and toluene sulfonic acid and allowed to stand at room temperature for twenty minutes to yield 3a,11otdiacetoxy 401,8,14 trimethyl 17 oxa D homo 18- nor-511,841,9 8,13a,l4fl-androstane-l7a-one.

EXAMPLE l1 3 3,1 I u-diacet0xy-4a,8,1 4-trimethyI-1 7 -0xa-D -h 0m0-1 8 n0r-5 41,8 ot,9,8,1 3 04,1 4B-andr0stane-1 7a-0ne 3,8, 110: dihydroxy 4a,8,l4 trimethyl 17 oxa D- homo 18 nor 5a,8a,9fl,13a,14,8 androstane 17a-one is acylated according to the procedure set forth in Example to yield 35,11a diacetoxy 4a,8,14 trimethyl- 17 oxa D homo 18 nor 5a,8a,9fi,13u,14,8 androstane-17a-one.

EXAMPLE 12 3 8,1 7aa-dihydroxy-4a,8,14-trimethyl-1 7-0xa-D-h0mo-1 8- nor-511,804,] 3 ct,] 4fi-andr0stane-1 1 -one A solution of 100 mg. of 40,8,14-trimethyl-17-oXa-D- homo 18 nor 5a,8ot,13u,l4;5' androstane 3,11,17atrione and 100 mg. of sodium borohydride in 10 ml. of absolute ethanol is stirred at room temperature for four hours. After decomposition of excess hydride with glacial acetic acid, the pH is adjusted to 2 with 5% hydrochloric acid and the solvent evaporated. The aqueous residue is extracted with ethyl acetate, which is washed until neutral, dried, and evaporated. Crystallization of the residue from acetone-hexane gives 3fi,17aa-dihydroxy- 4a,8,14-trimethyl-17-oxa-D-homo-18-nor 5a,8a,l3tx,l4fiandrostane-ll-one, M.P. 242-245 C. The analytical sample has M.P. 246-248 C., [e1 158 (chloroform).

Analysis.Calcd for C H O C, 71.96; H, 9.78. Found: C, 72.03; H, 9.89.

EXAMPLE 13 A solution of 105 mg. of 36,17aot-dihydroxy-4a,8,14- trimethyl-l7-oxa-D-homo-18-nor 5a,8a,13a,14,8 androstane-ll-one in 2 ml. of pyridine and 1 ml. of acetic anhydride is left at room temperature overnight. The reaction mixture is diluted with water and evaporated. The residue is taken up in ethyl acetate, which is washed with 5% hydrochloric acid and water, dried, and evaporated. Crystallization from methanol gives 54 mg. of 3,6,17aadiacetoxy-4a,8,14-trimethyl-17-oxa D homo 18 nor- 50L,80t,130t,14,8 androstane 11 one, M.P. 194197 C. Further recrystallization from methanol gives analytically pure material, M.P. 208-209 C., [04] 84 (methanol), 94 (chloroform).

Analysis.Calcd for C H O C, 69.09; H, 8.81. Found: C, 69.16; H, 8.82.

EXAMPLE 14 3 3-hydr0xy-4u,8,14 trimethyl-l 7 -0xa-D-h0mo 18 nor- 5ot,8a,13a,14,8-andr0stane-11,1 7 a-dione One hundred mg. of 4a,8,14-trimethyl l7-oxa-D-homo- 18-nor-5a, 8a,l3a,14;8-androstane 3,11,17a trione and mg. of sodium borohydride are added to 10 ml. of 2.5% ethanolic potassium hydroxide solution and stirred at room temperature for four and one-half hours. The excess borohydride is decomposed with glacial acetic acid and the solution acidified to pH 2 with 5% hydrochloric acid. The solvent is evaporated and the residue extracted with ethyl acetate, which is washed with saturated sodium chloride solution, dried, and evaporated to give 102 mg. of residue. Recrystallization from methanol gives 46 mg. of 3B-hydroxy-4ot,8,l4-trimethyl- 17-oxa-D-homo-18-nor 5a,8a,13a,14fi androstane 11, 17a-dione, M.P. 252-256 C. The analytical sample has M.'P. 255'257 C., [aj 16"6 (chloroform).

Analysis.-Calcd for C H O C, 72.38; H, 9.26. Found: C, 72.53; H, 9.25.

EXAMPLE 15 3B-acetoxy-4a,8,1 4 trimethyl-I7-oxa=D-h0m0-18-n0r-5a- 8a,13cc,1 7,8-andr0stane-1 I ,1 7a-di0ne A solution of 5-1 mg. of 3B-hydroXy-4a,8,14-trimethyll7-oxa-D-hom-oal8-nor 5a,8a,13a,l4,5 androstane 11, 17a-dione in 1 ml. of pyridine and 0.5 ml. of acetic anhydride is left overnight at room temperature. After addition of water the solution is evaporated to give 55 mg. of 3/3-acetoxy-4a,8,14-trimethyl-17-oxa-D-homo-18- nor-5u,8u,13a,14,6-androstane 11,17a dione. Two recrystallizations from methanol give analytically pure material, M.P. 287-290 C. (in vacuo), [a] 131 (chloroform).

Analysis.-Calcd for C H O C, 70.74; H, 8.78. Found: C, 70.67; H, 8.73.

While there have been described various embodiments of the invention, the compositions and methods described are not intended to be understood as limiting the scope of the invention, as it is realized that changes therein are possible and it is further intended that each element recited in any of the following claims is to be understood as referring to all equivalents for accomplishing substantially the same results in substantially the same or equivalent manner, it covering the invention broadly in whatever form its principle may be utilized.

What is claimed is:

1. A compound having the formula wherein R' is hydrogen; R is hydroxy or the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms; and together R and R' is 0x0 2. A compound in accordance with the formula of claim 1 having the name 3a-acetoXy-l1a-hydr-oxy-4a,8, l4-trimethyl-17-oxa-D-homo-18 nor 5a,8ot,9;9,130c,l4,3- androstane-17a-one.

3. A compound in accordance with the formula of claim 1 having the name 3a-acetoxy-4a,8,14-trimethyll7-oXa-D-homo-l8-nor-5a,8fi,9a,13a,14{3 androstane-ll, 17a-dione.

4. A compound in accordance with the formula of claim 1 having the name 35,11a-dihydroxy-4 ,8,14-trimethyl-17-oxa-D-homo-18-n0r-5u,8a,9;8,l3a,14,3 androstane-17a-one.

5. A compound in accordance with the formula of claim 1 having the name 40:,8,14-trimethyl-17-oXa-D- homo-l8-nor-5a,8a,9/3,13a,14B androstane-3,11,17a-trione.

6. A compound in accordance with the formula of claim 1 having the name 3a,11u-dihydroxy-4u,8,14-trimethyl-17-oXa D-homo-17-nor-5a,8a,9,8,13a,14(3 androstane-17a-one.

7. A compound in accordance with the formula of claim 1 having the name 404,8,14-trimethy1-17-oxa-D- hOmO-l8-DOI-5u,8a,1311,1413 androstane-3,11,17a-trione.

8. A compound in accordance with the formula of claim 1 having the name 3u-hydroxy-4a,8,l4-trimethyll7-0xa-D-homo-l8 nor 5a,8 x,13u,14,8 androstane-ll, 17a-dione.

9. A compound in accordance'with the formula of claim 1 having the name 3u-acetoXy-4a,8,14-trimethy1- 17-oXa-D-homo-18 nor 5a,8oc,l3on,l4fii androstane l1, 17a-dione.

107 A compound in accordance with the formula of claim 1 having the name 311,1la-diacetoxy-4a,8,l4-trimethyl-l7-oxa-D-homo-18-nor-5a,8a,9fl,1306,14 3 androstane-l7a-one.

11. A compound in accordance with the formula of claim 1 having the name 36,11u-diacetoxy-4a,8,14-trimethyl-l7-oxa-D-homo-l8-nor-5a,8a,9fi,13a,l4fi androstane-17a-one.

12. A compound in accordance with the formula of claim 1 having the name 3fl,l7aa-dihydroxy-4u,8,l4-trimethyl-17-oxa-D-homo-18 nor 5u,8oc,l3a,14fi androstane-l l-one.

13. A compound in accordance with the formula of claim 1 having the name 3B,17au-diacetoxy-4u,8,14-trimethyl-17-oxa-D-homo 18-nor 5m,8a,13u,14fl androstane-l l-one.

14. A compound in accordance with the formula of claim 1 having the name 3B-hydroXy-4a,8,14-trimethy1- 17-oxa-D-homo-l8-nor 5a,8a,13a,14[3 androstane 11, 17a-dione.

15. A compound in accordance with the formula of claim 1 having the name 3fi-acetoxy-4a,8,14-trimethyl- 17-oxa-D-homo-18-nor 5a,8u,13a,17,8 androstane ll, 17a-dione.

References Cited by the Examiner Krakower and Schwartz: American Chemical Soc., abstracts of papers (April 4, 1965), page 20F.

WALTER A. MODANCE, Primary Examiner.

JAMES A. PAT'IEN, Assistant Examiner. 

1. A COMPOUND HAVING THE FORMULA 